BCG Evidence to Recommendation Framework

Transcription

1 BCG Evidence to Recommendati Framework

2 Table 1 BCG vaccinati at birth vs. at 6 weeks SAGE Evidence to recommendatis framework i Detailed evidence related to the evidence to recommendati table can be found in the background papers preseed to the Strategic Advisory Group of Experts (SAGE) Immunizati in October Questi: Should the BCG vaccine be given to infas at birth or at the time of the first dose of the diphtheria tetanus and pertussis (DTP1) coaining vaccine at 6 weeks of age to mitigate the risk of severe TB disease, with special focus couries with a high burden of TB? Populati: Infas. Iervei: One dose of BCG vaccine given at birth. Comparis(s): One dose of BCG vaccine given at the same time as the first dose of DTP vaccine at the age of 6 weeks. Outcome: Prevei of severe TB disease in childhood (miliary, meningeal form ) and TB associated death Background: Prevei of TB relies two strategies: worldwide vaccinati with BCG, preferably at birth 2 and treatme of late TB Infecti 3 in HIV infected perss and young children coacts of TB cases. Despite its limitatis, BCG remains an importa tool for prevei of TB. WHO recommends that all infas in couries with a high burden of TB should receive the BCG vaccine as so as possible after birth 4, yet in many couries, vaccinati is delayed to be administered ccomitaly with the first peavale vaccine at the age of 6 weeks. The BCG Working Group revisited this curre recommendati csidering the evidence base around the timing of BCG vaccinati looking for any difference in terms of efficacy or safe between BCG vaccinati at birth and at 6 weeks of age. PROBLEM CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION Is the problem a setting by public health priori? The timing of BCG vaccinatis varies between and within couries, with delayed vaccinati (rather than at birth) extremely comm in many couries. Although often officially reported as The median BCG coverage amg infas across the 71 couries surveyed was 38% by 1 week of age; 75% by 6 weeks of age; 88% by 14 weeks of age and 93% by 52 weeks of age. 1 1 BCG Working Group report, available at accessed September accessed July accessed July WHO BCG Positi Paper

3 Table 1 BCG vaccinati at birth vs. at 6 weeks birth dose, BCG immunizati is usually delayed uil the DTP1 vaccine (around 6 weeks of age). BENEFITS & HARMS OF THE OPTIONS Benefits of the Are the desirable aicipated effects large? Harms of the Are the aicipated effects small? In comparis to birth dose, modelling of BCG co-administrati with DTP1 at 6 weeks of age was estimated to lead to 3,119 (95% UR: 125 7,643), or 1.8% (95% UR: 0.1%- 4.5%), increase in TB deaths. 6 BCG vaccinati in immunocompete individuals is csidered as safe. 7 Pediatric HIV infectis are decreasing and the probabili that a child is born to HIV- infected mother and is HIV-infected at the time of BCG vaccinati is now low. Early airetroviral therapy (ART) initiati before immunological and/or clinical progressi substaially reduces the risk of BCG-IRIS regial adenitis. As couries move to impleme more There is a pauci of evidence to assess the effectiveness and efficacy of BCG vaccinati at birth and at 6 weeks. 5 A coury example from South Africa, which has high HIV prevalence, is giving the priori to preve TB and therefore vaccinates all children. Innovatis such as HIV testing at birth and use of poi-of-care (POC) technologies may allow more rapid ideificati of HIV-infected infas in the near future, but there is currely very limited implemeati. 5 Uthman et al. Systematic review the effectiveness and efficacy of BCG against TB, unpublished, see SAGE Background documes 6 Roy et al. Mathematical modelling to estimate the impact of age of BCG vaccinati global paediatric TB mortali, unpublished, see SAGE Background documes. 7 Uthman et al. Systematic review the safe of BCG against TB and leprosy, unpublished, see SAGE Background documes 2

4 Table 1 BCG vaccinati at birth vs. at 6 weeks rapid ART initiati, occurrence of BCGemia and BCG IRIS is less likely. 1 Balance between benefits and harms What is the overall quali of this evidence for the critical outcomes? both neither Unclear Effectiveness of the included studies Very low Low comparis Moderate High Safe of the Balance between benefit & harms favor the (vaccinati at birth). There is a pauci of evidence the differences of effectiveness and safe of BCG vaccinati at birth and 6 weeks. 5,7 VALUES & PREFERENCES How certain is the relative importance of the desirable and outcomes? Values and preferences of the target populati: Are the desirable effects large relative to effects? included studies Very low Low Moderate High Importa y or Possibly importa y or babl y no importa y or importa y or known undesir able outcom es babl y Unc erta in babl y Vari es evidence was available by cducting a rapid review. formal analysis of preferences of target group been de, but it s assumed that (birth vaccine) is more preferable to the target group. Vaccinati at birth is an opportune time for BCG administrati as the infa is within the health system. If an infa is delivered at home, BCG vaccinati forms part of an iegrated visit to 3

5 Table 1 BCG vaccinati at birth vs. at 6 weeks the health cere for both infa and mother e.g. postnatal care of the mother and newborn. RESOURCE USE E Q Are the resources required small? What would be Costeffectiveness Increased Reduced Infas delivered in a health care facili can receive BCG vaccinati at birth from trained nurses/midwives. For infas delivered at home, they can receive a BCG vaccinati from trained nurses during their postnatal care visit for the mother and newborn or by outreach workers. Formal cost-effectiveness analyses have not been cducted, but BCG at birth reduces more disease and death. Therefore, the benefit overrides the cost of the vaccine. For those born at home, attending clinic immediately after birth to receive BCG would not be csidered an additial visit but, is a recommended coact for receiving other maternal and child health (MCH) postnatal care packages. Implemeing a BCG birth dose, BCG vaccinati at birth should be promoted as per existing WHO guidelines 8 or during the postnatal care visit for the mother and newborn. 9 8 WHO. Pregnancy, childbirth, postpartum and newborn care: a guide for esseial practice WHO. WHO recommendatis postnatal care of the mother and newborn

6 Table 1 BCG vaccinati at birth vs. at 6 weeks the impact health inequities? particularly in resource-cstrained settings, is expected to reduce health inequities. ACCEPTABILITY Which opti is acceptable to key stakeholders (Ministries of Health, Immunizati Managers)? Which opti is acceptable to target group? Iervei Com paris Both Neit her Unclear Iervei Com paris Both Neit her Unclear Administering BCG at birth is an acceptable opti to key stakeholders as it requires no change to the curre immunizati schedule. Ensuring early protecti of infas is likely to be acceptable to the target group. Shifting BCG vaccinati to 6 weeks would result in as many as 5-6 vaccinatis in e visit, which could be challenging to impleme. FEASIBI LITY Is the feasible to impleme? bab ly Uncer tai n ba bly Varie s The is feasible if linked with postnatal care of the mother and newborn visit and if coordinated between MCH and EPI natial BCG vaccinati at birth should be promoted as per existing WHO guidelines 10 or during the postnatal care visit for the mother and newborn WHO. Pregnancy, childbirth, postpartum and newborn care: a guide for esseial practice WHO. WHO recommendatis postnatal care of the mother and newborn

7 Table 1 BCG vaccinati at birth vs. at 6 weeks Balance of Undesirable clearly outweigh desirable Undesirable probably outweigh desirable immunizati programmes. Importa opportunities exist to iegrate HepB birth dose; cduct birth registrati; provide a vaccinati card and key messages about vaccinati to the caregiver. The balance between desirable and is closely balanced or n Due to the large BCG vial size (10-20 doses), wastage is to be expected. However, the importance of giving the vaccine should override wastage ccerns. Desirable probably outweigh Desirable clearly outweigh Type of recommendati We recommend the We suggest csidering recommendati of the We recommend the comparis We recommend against the and the comparis Only in the coext of rigorous research Only with targeted mitoring and evaluati Only in specific coexts or specific (sub)populatis 6

8 Table 1 BCG vaccinati at birth vs. at 6 weeks Recommendati (text) In couries or settings with a high incidence of TB and/or leprosy, a single dose of BCG vaccine should be given to neates at birth, or as so as possible thereafter, for prevei of TB and leprosy disease. If it cannot be given at birth, it should be given at the earliest opportuni thereafter and should not be delayed. Any delay in vaccinati may lead to opportunities for known or unknown exposure to TB or leprosy infected coacts. As newborns are also recommended to receive their first dose of hepatitis B vaccine as so as possible after birth, ideally within 24 hours, co-administrati of BCG with the hepatitis B birth dose is strgly recommended as it is safe to do so. If the birth dose was missed, catch-up vaccinati of unvaccinated older infas and children is recommended since evidence shows it is beneficial. Catch-up vaccinati should be de at the earliest cvenie encouer with the health-care system to minimize known or unknown exposure to TB or leprosy infected coacts. Implemeati csideratis Ensure that health care workers have received the appropriate training for vaccine administrati. Mitoring and evaluati grammes should mitor the timeliness of BCG vaccinati. Research priorities Studies the effectiveness and safe of BCG vaccinati at birth and 6 weeks. i This Evidence to Recommendati table is based the DECIDE Work Package 5: Strategies for communicating evidence to inform decisis about health system and public health s. Evidence to a recommendati (for use by a guideline panel). 7

9 Table 2 Need for revaccinati SAGE evidence to recommendatis framework i Detailed evidence related to the evidence to recommendati table can be found in the background papers preseed to the Strategic Advisory Group of Experts (SAGE) Immunizati in October Questi: Is there the need for a BCG revaccinati following primary BCG immunizati? Populati: Immunocompete individuals. Iervei: BCG revaccinati following primary BCG immunizati. Comparis(s): Primary BCG immunizati. Outcome: Prevei of TB infecti and disease Background: Primary infa BCG vaccinati offers csiste durable protecti for up to 10 years. There is some evidence of lger protecti. 2 Therefore, there is a poteial need for BCG revaccinati. BCG revaccinati is safe in Mycobacterium tuberculosis infected and uninfected populatis. There is a lack of evidence from randomized corolled trials and retrospective cohort and case-corol studies demstrating the efficacy and effectiveness of BCG revaccinati in adolesces and adults after primary BCG vaccinati in infancy for protecti against TB disease. Due to absence of evidence, BCG revaccinati is not csidered cost-effective. Further research is warraed to explore whether certain sub-groups of age, geographic or M. tuberculosis exposure categories would benefit from revaccinati. PROBLEM CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION Is the problem a setting by public health priori? BCG vaccinati offers csiste durable protecti against TB for up to 10 years. 3 Data protecti beyd 15 years are limited. 2 If effective, BCG revaccinati could be a low-cost tool for TB corol, particularly with waning protecti WHO/UNICEF Joi Reporting Form (JRF) data from 2016 show that 6 couries have BCG revaccinati in their routine immunizati schedule. 5 1 SAGE Working Group report, available at accessed September Mangtani et al. The durati of protecti of school-aged BCG vaccinati in England: a populati -based case corol study. Iernatial Journal of Epidemiology, dyx Available at: 3 Abubakar et al., tecti by Bacillus Calmette-Guérin vaccinati against tuberculosis beyd 10 years: Systematic Review and Meta-Analysis [Under review]. 5 WHO/UNICEF joi reporting process. Available at accessed July

10 Table 2 Need for revaccinati in adolesces and adults vaccinated at birth. 4 BENEFITS & HARMS OF THE OPTIONS Benefits of the Are the desirable aicipated effects large? Harms of the Are the aicipated effects small? The body of evidence to evaluate BCG revaccinati against M. tuberculosis indicates that BCG revaccinati is not effective. BCG revaccinati is safe in M. tuberculosis unexposed and exposed / infected, and HIV uninfected people. A double-blind RCT of BCG (Glaxo) in Malawi showed no protective benefit of revaccinati compared to placebo against cfirmed TB disease (IRR 1.43; 95% CI ). 6 In the BCG-REVAC RCT in Brazil, 7,8,9, using TB incidence as the primary outcome, the study found that amg children aged 7-14 years initially vaccinated at birth and then revaccinated with BCG (Moreau) at school age, overall vaccine efficacy was 9% (95% CI: %) after 0-5 years of follow-up and 12% (95% CI: -2-24%) after extended follow-up for 9 Error! Bookmark not defined. years. Adverse reactis to BCG (Moreau-Rio de Janeiro substrain) revaccinati in 71,000 Brazilian schoolchildren were rare. skin tests were carried out, but right upper arms of all children were inspected for a BCG scar. Children were not vaccinated if they had two scars or unclear scar readings. significa difference in the rate of adverse reactis was observed between primary BCG vaccinati and BCG revaccinati Plotkin SA, Orenstein W, Offit PA. Vaccines, 6th Editi p Karga Prevei Trial Group. Randomised corolled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevei of leprosy and tuberculosis in Malawi. Lancet, (9019): p Rodrigues LC et al., Effect of BCG revaccinati incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial. Lancet Oct 8;366(9493): Epub 2005 Aug Barreto ML, Pereira SM, Pilger D, Cruz AA, Cunha SS, Sa'Anna C, et al. Evidence of an effect of BCG revaccinati incidence of tuberculosis in school-aged children in Brazil: Secd report of the BCG-REVAC cluster-randomised trial. Vaccine [Iernet]. Elsevier Ltd; 2011;29(31): Available from: 9 Barreto ML, Pilger D, Pereira SM, Genser B, Cruz AA, Cunha SS, et al. Causes of variati in BCG vaccine efficacy: Examining evidence from the BCG REVAC cluster randomized trial to explore the masking and the blocking hypotheses. Vaccine [Iernet]. Elsevier Ltd; 2014;32(30): Available from: 10 Dourado I et al., Rates of adverse reactis to first and secd doses of BCG vaccinati: results of a large communi trial in Brazilian schoolchildren. I J Tuberc Lung Dis Apr;7(4):

11 Table 2 Need for revaccinati Balance between benefits and harms What is the overall quali of this evidence for the critical outcomes? both neither Unclear Effectiveness of the included studies Very low Low comparis Moderate High Safe of the The comparis is favored when balancing the benefits and harms. The evidence has low quali. The evidence has low quali. In an observatial study of BCG (Danish; Glaxo and Behringwerke) revaccinati in 2,997 Swedish school children reported the reactogenici profile was similar to that of primary BCG vaccinati. 11 VALUES & PREFERENCES How certain is the relative importance of the desirable and outcomes? Values and preferences of the target included studies Very Moderate Low low High Importa y or Possibly importa y or babl y no importa y or importa y or known undesir able outcom es babl y Unc erta in babl y Vari es evidence available though it is assumed that in general, there is no importa y or. A review of literature retrieved no evidence the values and preferences of the target populati. 11 Böttiger M et al., A comparative study of Danish (Statens Serum Institut), Glaxo and Behringwerke vaccines--revaccinati of schoolchildren. J Biol Stand Jan;11(1):

12 Table 2 Need for revaccinati RESOURCE USE populati: Are the desirable effects large relative to effects? Are the resources required small? Costeffectiveness But it is assumed that the revaccinati is not preferable by the target group. Assessme of the values and preferences is very coext specific and, in case no data are available, couries are asked to cduct these assessmes in their specific setting. Additial resources will be needed to administer/impleme revaccinati. If couries also choose to carry out tuberculin skin testing (TST) prior to revaccinati, additial costs will be incurred. There is a lack of evidence for the effectiveness of revaccinati. Therefore it is n if BCG revaccinati is cost-effective. Dye (2013) 12 modelled vaccine efficacy and cost-effectiveness when offering BCG (any vaccine) revaccinati to TST negative adolesces after primary vaccinati. The incremeal cost per year of health life recovered was USD, and this costeffectiveness doubled if additial benefits of transmissi prevei were csidered. When allowing for Cvei of doing a TST prior to revaccinati will add csiderable costs. In additi, there are freque tuberculin shortages. 12 Dye C. Making wider use of the world's most widely used vaccine: Bacille Calmette Guérin revaccinati recsidered J. R. Soc. Ierface 2013 Jul 31;10(87). 4

13 Table 2 Need for revaccinati EQUITY What would be the impact health inequities? both direct effects and indirect reducti of transmissi and assuming 80% BCG revaccinati efficacy, the model suggests BCG revaccinati of TST negative adolesces could avert 17% of TB cases. It is not expected that the has a huge impact of the health inequities. ACCEPTABILITY FEASIBI LITY Which opti is acceptable to key stakeholders (Ministries of Health, Immunizati Managers)? Which opti is acceptable to target group? Is the feasible to impleme? Increased Reduced Iervei Com paris Both Neit her Unclear Iervei Com paris Both Neit her bab ly Unclear Uncer tai n ba bly Varie s Revaccinati is likely not acceptable to the key stakeholders given the increased costs and limited additial benefit for the target populati. Ensuring adequate protecti with the least number of injectis is likely the most acceptable opti to the target populati. Revaccinati is feasible to impleme with little difficul to add it in the schedule. However,given the limited benefit of 5

14 Table 2 Need for revaccinati Balance of Undesirable clearly outweigh desirable Undesirable probably outweigh desirable the, it is not advisable to impleme the but to focus resources the administrati of the primary BCG vaccinati and cduct of coact tracing for coagious TB cases. The balance between desirable and is closely balanced or n Desirable probably outweigh Desirable clearly outweigh Type of recommendati We recommend the We suggest csidering recommendati of the We recommend the comparis We recommend against the and the comparis Only in the coext of rigorous research Only with targeted mitoring and evaluati Only in specific coexts or specific (sub)populatis 6

15 Table 2 Need for revaccinati Recommendati (text) There is little additial benefit of repeat BCG vaccinati against TB or leprosy. Therefore, revaccinati is not recommended even if the TST reacti or result of an IGRA is negative. The absence of a BCG scar after vaccinati is not indicative of a lack of protecti and is not an indicati for revaccinati. Implemeati csideratis n/a Mitoring and evaluati n/a Research priorities Additial lger-term studies should be cducted to explore vaccine efficacy and effectiveness and the need of revaccinati in differe subgroups of the populati. Research required the revaccinati of TST positives. i This Evidence to Recommendati table is based the DECIDE Work Package 5: Strategies for communicating evidence to inform decisis about health system and public health s. Evidence to a recommendati (for use by a guideline panel). 7

16 Table 3 Selective vaccinati SAGE evidence to recommendatis framework i Detailed evidence related to the evidence to recommendati table can be found in the background papers preseed to the Strategic Advisory Group of Experts (SAGE) Immunizati in October Questi: What is the incremeal effectiveness of vaccinating infas universally versus selectively in low burden TB couries (annual TB notificati rate of 100 cases of all TB forms per milli populati)? Populati: Immunocompete infas in couries with low burden of TB Iervei: Routine administrati of a BCG vaccine to selective infas at increased risk of TB in low TB endemic couries. Comparis(s): Routine administrati of a BCG vaccine universally to all infas in low TB endemic couries. Outcome: TB infecti and disease As the incidence of TB coinues to decline in developed couries, selective vaccinati strategies in high-risk populatis are being csidered as an alternative to universal BCG vaccinati. 2,3,4,5 However, selective immunizati programmes depend heavily the abili to ideify and reach the target populati. 6 The target populati could be newborns of pares (or with close coacts/relatives) with previous TB, leprosy, or Buruli ulcer disease, newborns from immigra populatis from couries with high incidence of TB or leprosy, newborns from any other locally ideified risk group for TB, leprosy and Buruli ulcer disease. 1 BCG working group Report, available at accessed September BCG World Atlas, 2nd Editi. Available: accessed July Dierig A, Tebruegge M, Krivec U, Heininger U, Ritz N. Curre status of Bacille Calmette Guerin (BCG) immunisati in Europe - A ptbnet survey and review of curre guidelines. Vaccine [Iernet]. Elsevier Ltd; 2015;33(38): Available: 4 Tu H-AT, Vu HD, Rozenbaum MH, Woerdenbag HJ, Postma MJ. A review of the literature the ecomics of vaccinati against TB. Expert Rev Vaccines. 2012;11(3): Hersh AL, Tala-Heikkilä M, Tala E, Tostes ANA, Fordham v Reyn C. A cost-effectiveness analysis of universal versus selective immunizati with Mycobacterium bovis bacille Calmette-Guérin in Finland. I J Tuberc Lung Dis. 2003;7(1): Feiring B, Laake I, Molden T, Haberg SE, kleby H, Seterelv SS, et al. Do selective immunisati against tuberculosis and hepatitis B reach the targeted populatis? A natiwide register-based study evaluating the recommendatis in the rwegian Childhood Immunisati gramme. Vaccine [Iernet]. Elsevier Ltd; 2016;34(17): Available from: 1

17 Table 3 Selective vaccinati PROBLEM BENEFITS & HARMS OF THE OPTIONS Benefits of the Are the desirable aicipated effects large? Harms of the CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION Is the problem a setting by public health priori? In couries with a low burden of TB, some limit BCG vaccinati to neates and infas of recognized high-risk groups for TB or to tuberculin-skin-test negative older Due to the curre flow of refugees from high TB endemic couries to low TB endemic couries, there is an going discussi about how best to preve TB. The evidence of the benefits of universal BCG vaccinati in low endemic settings is n. While several meta-analyses of available data have shown that the BCG vaccines can preve a significa proporti of the cases of meningeal and miliary TB, the incidence of both of these cditis is very low in low burden couries, even without BCG vaccinati. 1 Nevertheless, universal vaccinati might preve the few TB cases but leads to adverse eves. There are no studies comparing the safe of routine administrati of a Based data from the 2016 Joi Reporting Form (data from 194 member states), 143 member states recommend universal birth dose of BCG; 13 couries give universal vaccinati later during childhood; 21 couries did not have BCG vaccinati in their routine schedule and 17 couries recommend selective BCG vaccinati. Studies report that the comparis of vaccinati of specific groups in combinati with active case finding is effective as well. 7,8 However, the amou of programmatic evidence for the latter is low, as few couries have fully reported the comparis results when they have changed to selective BCG vaccinati. Rates of adverse eves following immunizati (AEFI) would be fewer if selective vaccinati is chosen. 7 Romanus V, Selective BCG vaccinati in a coury with low incidence of tuberculosis. Euro Surveill. 2006;11(3): Trnka L et al., Six years' experience with the discoinuati of BCG vaccinati. 1. Risk of tuberculosis infecti and disease. Tuber Lung Dis Jun;74(3):

18 Table 3 Selective vaccinati Are the aicipated effects small? BCG to all infas or to selective infas at increased risk of TB. The harms of the (selective strategy) include missing some high risk individuals. In general, universal BCG vaccinati in low TB endemic couries is safe. Balance between benefits and harms What is the overall quali of this evidence for the critical outcomes? both neither Unclear Effectiveness of the included studies Very low Low comparis Moderate High Safe of the The comparis of routine administrati of a BCG vaccine to all infas in low TB endemic couries to BCG vaccinati of selective infas at increased risk of TB in low endemic couries is unclear when balancing the benefits and harms. Either opti relies reaching groups who may not participate fully in the health care system. There are no published randomized corol trials or case-corol studies of the results - effectiveness or safe - of selective BCG vaccinati in low burden couries. VALUES & PREFEREN How certain is the relative importance of the desirable and included studies Very Moderate Low low High Importa y or Possibly importa y or babl y no importa y or importa y or known undesir able outcom es Based a rapid review, no evidence was available though it is assumed that, in general, there is no importa y or. The possible effect of stigma must be csidered; even though providing the vaccine to high-risk groups can be seen as a benefit, some members of the target group may csider it to be TB discriminatory and produce stigma, especially as BCG vaccinati leaves a 3

19 Table 3 Selective vaccinati outcomes? Values and preferences of the target populati: Are the desirable effects large relative to effects? babl y Unc erta in babl y Vari es Based a rapid review, no evidence was available though it is assumed that, in general, there is no importa desirable effect. scar in most cases. However, there is a need to balance the stigma of selective BCG vaccinati and the risk of coracting TB. RESOURCE USE Are the resources required small? Cost- Iervei: There will be costs associated with the ideificati of infas at increased risk of TB and providing the vaccine to them in a timely fashi. Comparis: Although no additial health care visits are needed, additial resources in respect to costs will be required for administrati of universal BCG vaccinati in low endemic couries. Although universal BCG vaccinati BCG vaccine shortages could particularly impact couries that retain universal vaccinati, and universal vaccinati could inadvertely coribute to cause or coribute to shortages. Reviews by Trunz et al. (2006) 9 and Tu et al. (2012) 4 provided a worldwide perspective 9 Trunz BB et al. Effect of BCG vaccinati childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessme of cost-effectiveness. Lancet Apr 8;367(9517):

20 Table 3 Selective vaccinati EQUITY ACCEPTABILITY effectiveness What would be the impact health inequities? Which opti is acceptable to key stakeholders (Ministries of Health, Immunizati Managers)? Which opti is acceptable to target group? Reduced Iervei impact Com paris Both Increased Neit her Unclear Iervei Com paris Both Neit her Unclear in couries with low TB incidence does offer protecti in paediatric populatis, the additial protecti cferred by universal strategies is comparatively small and less cost-effective when compared to targeted vaccinati of infas at increased risk of TB. The possible effect of stigma must be csidered as some members csidered at increased risk of TB may deem it to be discriminatory and actually produce stigma, even though providing the vaccine can be seen as a benefit, particularly as it provides an opportuni for a health visit coact. In low TB couries, universal BCG vaccinati is not cost effective. Therefore, the is likely to be more acceptable to key stakeholders. Ensuring adequate protecti is likely the most acceptable opti to the target populati. the costs and benefits of the BCG vaccine and ccluded that vaccinati remained costeffective in high TB incidence settings. 5

21 Table 3 Selective vaccinati FEASIBILITY Is the feasible to impleme? Balance of bab ly Uncer tai n ba bly Varie s Undesirable clearly outweigh desirable Undesirable probably outweigh desirable The feasibili will depend, in part, the nature of the coury s health care system and how they offer health care to immigras, refugees, and those living in pover. In low TB endemic couries, BCG should be given selectively to infas at increased risk of TB. However, infas at increased risk of TB are often immigras and refugees who may have very limited access to health care in their new coury. The balance between desirable and is closely balanced or n Desirable probably outweigh Desirable clearly outweigh 6

22 Table 3 Selective vaccinati Type of recommendati We recommend the We suggest csidering recommendati of the We recommend the comparis We recommend against the and the comparis Only in the coext of rigorous research Only with targeted mitoring and evaluati Recommendati (text) Only in specific coexts or specific (sub)populatis Couries with a low incidence of TB or leprosy may choose to selectively vaccinate neates in recognized risk groups for developing disease. High-risk groups to be csidered for vaccinati include the following: Neates to pares (or other close coacts/relatives) with previous TB or leprosy Neates in immigra populatis from couries with high incidence of TB and/or leprosy. Neates in any other locally ideified risk group for TB and/or leprosy. In a few couries with low TB incidence, BCG vaccinati is largely replaced by iensified case detecti, coact tracing and supervised early treatme. 7

23 Table 3 Selective vaccinati Implemeati csideratis Mitoring and evaluati Switching from universal to selective risk group vaccinati at birth Couries with declining rates of TB are encouraged to periodically evaluate the epidemiology of TB and csider if a switch from universal vaccinati to selective risk group vaccinati would be appropriate. Before switching to selective BCG vaccinati, couries should csider the impact of a switch prevei of leprosy. Csiderati may be given also to other mycobacterial infectis, as well as any poteial NSE of BCG vaccinati all-cause infa mortali. When csidering switching from universal to selective risk group vaccinati, an efficie disease surveillance system capable of showing the curre average annual rate of smear-positive pulmary TB cases is a prerequisite. Additial data shall be taken io csiderati, in particular the average annual rate of tuberculous meningitis in children aged under five years and/or the average annual risk of tuberculous infecti in children and should be mitored. Finally the epidemiological situati for leprosy should be assessed through both routine notificati data and especially active screening activities. The burden of other mycobacterial infectis such as Buruli ulcer disease in the coury could be also reviewed. The actual epidemiology of TB in coury, particularly meningeal and miliary TB amg children and adolesces Cost data according to the structure of the health care system Research priorities Feasibili studies by health care system and structure Cost-benefit studies i This Evidence to Recommendati table is based the DECIDE Work Package 5: Strategies for communicating evidence to inform decisis about health system and public health s. Evidence to a recommendati (for use by a guideline panel). 8

24 Table 4 BCG vaccinati against leprosy SAGE evidence to recommendatis framework i Detailed evidence related to the evidence to recommendati table can be found in the background papers preseed to the Strategic Advisory Group of Experts (SAGE) Immunizati in October Questi: Should BCG be recommended, over no vaccinati, to immunocompete individuals to mitigate the burden of leprosy in leprosyendemic couries? Populati: Immunocompete individuals. Iervei: BCG vaccinati for infas. Comparis(s): vaccinati in the coext of routine leprosy corol s. Outcome: Leprosy disease. Background: Although the fight against leprosy has gained csiderable success, with an eliminati target set in 2000, more than 200,000 cases were notified in The detecti rate of the disease (a proxy of incidence rate) is ly slightly declining at a rate of about 4% per year. 2 Early diagnosis and complete treatme with multi-drug therapy (MDT) remain the key strategies for reducing disease burden. Although not specifically indicated for prevei of leprosy, there is strg evidence that BCG vaccinati has coributed to the decline in the incidence of the disease 3. Despite known evidence the effectiveness of BCG to preve leprosy, there are no WHO recommendatis for use of BCG for the prevei of leprosy. Several studies from high burden couries have examined the efficacy/ effectiveness of other vaccines and the combinati of post-exposure prophylaxis with BCG at birth and/or with BCG revaccinati. PROBLEM CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION Is the problem a setting by public health priori? Leprosy is an infectious disease with importa clinical, social, and public health. BCG vaccinati has been associated with reductis in the incidence of With ly partial efficacy of a chemoprophylaxis regimen, the availabili of a vaccine becomes an importa tool. The efficacy of BCG is variable (20-90%) taking io accou differe factors (e.g. age at vaccinati, clinical form, number of doses, pe of study, the latitude of study area) accessed September Weekly Epidemiological Record 2012, 3 Setia et al, The role of BCG in prevei of leprosy: a meta-analysis. Lancet Infect Dis Mar;6(3): Merle CS1, Cunha SS, Rodrigues LC. BCG vaccinati and leprosy protecti: review of curre evidence and status of BCG in leprosy corol. Expert Rev Vaccines Feb 1

25 Table 4 BCG vaccinati against leprosy leprosy. BENEFITS & HARMS OF THE OPTIONS Benefits of the Are the desirable aicipated effects large? Harms of the Are the aicipated effects small? Balance between benefits and harms comparis both neither Unclear In 5 trials, the efficacy of BCG vaccine against leprosy was 20-80% and the effectiveness in 6 cohort studies was 41-62% and 20-90% in 17 case-corol studies, respectively. 5 Evidence indicates BCG at birth is effective for preveing future leprosy infecti. One RCT found effects of a single dose rifampicin (SDR) greater in perss who also received childhood BCG (OR 0.20 (95% CI )). 6 Evidence does not support an increased safe risk for BCG vaccinati in a populati with a high leprosy burden. Infas known to be HIV-infected with or without symptoms of HIV infecti should not receive BCG vaccinati. Evidence of the protective efficacy and effectiveness for BCG vaccine given in infancy is given. In corast, evidence adverse The evidence for BCG re-vaccinati (two RCTs) is incsiste and data adverse eves are limited. 7 There is limited evidence of protective efficacy of revaccinati of BCG against leprosy. 5 Smith and Saunders Leprosy. BMJ Clin Evid. Jun 28;2010. pii: Shuring et al., tective effect of the combinati BCG vaccinati and rifampicin prophylaxis in leprosy prevei. Vaccine v 23;27(50): Cunha SS et al. BCG Revaccinati Does t tect Against Leprosy in the Brazilian Amaz: A Cluster Randomised Trial. PLoS Negl Trop Dis Feb 13;2(2):e167. 2

26 Table 4 BCG vaccinati against leprosy eves is limited. What is the overall quali of this evidence for the critical outcomes? Effectiveness of the included studies Very low Low Moderate High Safe of the included studies Very Moderate Low low High Effects of vaccinati risk of leprosy Comparis Findings Quali BCG at birth vs. no BCG or placebo Pooled OR 0.45 ( ) from Syst.Review 8 Moderate BCG at birth plus killed M. leprae vs. placebo 9 BCG plus killed M. leprae vs. BCG ale 10 BCG revaccinati in coacts vs. no BCG revaccinati 7 RRR 64% (50-74%) RR 1.06 (0.62 to 1.82) and RRR 56% (27-74%) RR 0.51 ( ), RR 0.99 ( ), Moderate Low Low ICRC vaccine vs. RRR 66% (48- placebo 11 77%) Mycobacterium w vaccine vs placebo 12 OR 0.61 ( ) and RRR 26% (1.9-44%) Moderate Moderate VALUES & PREFERENCES How certain is the relative importance of the desirable and outcomes? Importa y or Possibly importa y or babl y no importa y or importa y or known undesir able outcom es evidence available although it is assumed that, in general, there is no importa y or. In the coext of implemeati, communicati strategies of BCG vaccinati against TB could be used. Whether some individuals are ccerned about the theoretical risk of disseminated BCG disease or systemic BCG-itis to such an exte as to refuse vaccinati is unknown. 8 Richardus JH and Oskam L. tectig people against leprosy: chemoprophylaxis and immunoprophylaxis. Clin Dermatol Jan-Feb;33(1): Cvit J, et al. Immunoprophylactic trial with combined Mycobacterium leprae/bcg vaccine against leprosy: preliminary results. Lancet 1992; 339: Karga Prevei Trial Group. Randomised corolled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevei of leprosy and tuberculosis in Malawi. Lancet 1996:348: Deo MG, et al. Aileprosy poteials of ICRC vaccine. A study in paties and healthy volueers. Il. J. Lrpr. Other Mycobact. Dis. 1983; 51: Sharma P, et al. Immunoprophylactic effects of the ai-leprosy Mw vaccine in household coacts of leprosy paties: clinical field trials with a follow up of 8-10 years. Lepr. Rev. 2005; 76:

27 Table 4 BCG vaccinati against leprosy RESOURCE USE Values and preferences of the target populati: Are the desirable effects large relative to effects? Are the resources required small? babl y Unc erta in babl y Vari es research evidence was ideified. Costs of BCG at birth are likely to be mainly related to the cost of the vaccine. In couries with high TB endemici, there is no need for extra resources for BCG as a tool to preve leprosy. However, if BCG vaccinati discoinues, there may be additial costs. research evidence was ideified. Given the affordabili of the BCG vaccine, couries will need to csider whether the BCG vaccine is a priori to fund. However, there is an additial benefit of the BCG vaccine being effective in the prevei of two diseases. EQUITY ACCEPTABI LITY What would be the impact health inequities? Which opti is acceptable to key stakeholders (Ministries of Health, Costeffectiveness Increased Reduced Iervei Com paris Both Neit her Implemeing BCG vaccine, in particular in resource-cstrained settings, is expected to reduce health inequities related to prevei of leprosy. Unclear research evidence was ideified. Administering of the BCG vaccine against leprosy is assumed to be an acceptable opti to key stakeholders. 4

28 Table 4 BCG vaccinati against leprosy Immunizati Managers)? Which opti is acceptable to target group? Iervei Com paris Both Neit her Unclear research evidence was ideified. However, in some settings vaccinati programs are already performed and appear acceptable. Increasing protecti of the populati against leprosy by BCG vaccinati is likely to be acceptable to the target group. FEASIBILITY Is the feasible to impleme? bab ly Uncer tai n ba bly Varie s The is feasible if coordinated between maternal child health and EPI natial immunizati programmes. Balance of Undesirable clearly outweigh desirable Undesirable probably outweigh desirable The balance between desirable and is closely balanced or n Desirable probably outweigh Desirable clearly outweigh 5

29 Table 4 BCG vaccinati against leprosy Type of recommendati We recommend the We suggest csidering recommendati of the We recommend the comparis We recommend against the and the comparis Only in the coext of rigorous research Only with targeted mitoring and evaluati Recommendati (text) Only in specific coexts or specific (sub)populatis In couries or settings with a high incidence of TB and/or leprosy, a single dose of BCG vaccine should be given to neates at birth, or as so as possible thereafter, for prevei of TB and leprosy disease. If it cannot be given at birth, it should be given at the earliest opportuni thereafter and should not be delayed. Any delay in vaccinati may lead to opportunities for known or unknown exposure to TB or leprosy infected coacts. As newborns are also recommended to receive their first dose of hepatitis B vaccine as so as possible after birth, ideally within 24 hours, co-administrati of BCG with the hepatitis B birth dose is strgly recommended as it is safe to do so. If the birth dose was missed, catch-up vaccinati of unvaccinated older infas and children is recommended since evidence shows it is beneficial. Catch-up vaccinati should be de at the earliest cvenie encouer with the health-care system to minimize known or unknown exposure to TB or leprosy infected coacts. Implemeati csideratis BCG vaccinati relies the assumpti of BCG availabili and that it is already routinely administered as part of the natial immunizati programme. Mitoring and evaluati There might be the need to impleme a mitoring system for adverse eves if other vaccines will be used (BCG adverse eves mitoring already part of the EPI) 6

30 Table 4 BCG vaccinati against leprosy Research priorities Trials new and existing vaccines including studies LepVax, a new sub-unit vaccine are needed. Any novel TB vaccines should also be evaluated for leprosy prevei and vice versa. i This Evidence to Recommendati table is based the DECIDE Work Package 5: Strategies for communicating evidence to inform decisis about health system and public health s. Evidence to a recommendati (for use by a guideline panel). 7

31 Table 5 BCG efficacy and effectiveness SAGE evidence to recommendatis framework i Detailed evidence related to the evidence to recommendati table can be found in the background papers preseed to the Strategic Advisory Group of Experts (SAGE) Immunizati in October Questi: Should BCG be recommended at birth, over no vaccinati, to immunocompete infas based the evidence for BCG efficacy and effectiveness to mitigate against various forms of tuberculosis (TB)? Populati: Immunocompete infas. Iervei: BCG vaccinati at birth. Comparis(s): vaccinati. Outcome: tecti against various forms of TB. Background: The BCG vaccine is e of the most widely used vaccines and based previous available evidence, it preves severe forms of tuberculosis (TB) in children, known to be most pre to disseminated TB. BCG vaccinati is recommended by the WHO for all infas, as so as possible after birth, in couries with a high burden of TB. 2 Additial TB prevei strategies include treatme of late TB Infecti in HIV infected perss and chemoprophylaxis for young child coacts of adults with pulmary TB (PTB). 3 Rece research has extensively evaluated the efficacy and effectiveness of BCG vaccine against various forms of TB (TB infecti, PTB, severe disease), and this evidence is importa to guide curre policy and practice regarding use of BCG vaccine for the mitigati of various forms of TB. CRITERIA JUDGEMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION PROBLEM Is the problem a public health priori? by setting The incidence of TB has fallen by an average of 1.5% per year since Decline in TB incidence is slow, falling average by ~1.5% per year since 2000, and TB coinues to be e of the top 10 causes of morbidi and mortali globally In 2015, 87% of new TB cases occurred in the 30 high TB burden couries, however TB is reported in all regis and couries. Six couries accoued for 60% of the new TB cases: India, Indesia, China, Nigeria, Pakistan, and South Africa. 1 Working Group Report, BCG Working Group, available at accessed September WHO BCG Positi Paper accessed July

32 Table 5 BCG efficacy and effectiveness BENEFITS & HARMS OF THE OPTIONS Benefits of the Are the desirable aicipated effects large? (10.4 milli new cases and 1.8 milli deaths in 2015), with little likelihood of achieving the SDG at curre rate of decline in incidence. 4 Rece evidence of the additial protective effects of BCG vaccinati against TB infecti, progressi to active TB disease, pulmary TB and death has implicatis its overall effect the corol of TB.A systematic review and meta-analysis of 18 RCTs comparing vaccinated with unvaccinated participas, provided evidence BCG vaccine efficacy (VE) against severe forms of TB, and against PTB as follows 5. Efficacy against miliary & meningeal TB (severe disseminated TB): Pooled VE was 85% overall (95% CI 69 92%); efficacy was higher with neatal BCG (VE 90%), and for BCG given to TST negative school age children (VE 92%); VE was low in older children and adults. Efficacy against Pulmary TB: An estimated 25% of the global populati today has late TB infecti, which pose a big challenge to the corol or eliminati of TB in this generati. In Mangtani et al meta-analysis of 18 RCTs, the effect of latitude BCG efficacy/effectiveness was evaluated. tecti against PTB, efficacy appeared to be higher in settings further from the equator (latitude > 40 o RR 0.32, 95% CI versus latitude 0 o - <20 o RR 0.78, 95% CI ), however closer examinati of the specific populatis included in differe latitudes varied by age at vaccinati and by stringency of TST testing for older children and adults, as such this finding is ierpreted with cauti. 5 Findings of higher VE at high latitude settings may be related to inclusi of individuals who were not already mycobacteria exposed. The 5 studies from latitude 20 o 40 o were a mixture of school age or older participas, with mixture of stringe TST testing (3 4 WHO. 5 Mangtani P, Abubakar I, Ariti C, Beyn R, Pimpin L, Fine PEM, et al. tecti by BCG vaccine against tuberculosis: A systematic review of randomized corolled trials. Clin Infect Dis. 2014;58(4):

33 Table 5 BCG efficacy and effectiveness Pooled VE for birth BCG across 5 RCTs was 59% (95% CI 42-71%) VE for BCG given to TST negative school age children across 4 RCTs was 74% (95% CI 63-82%) tecti in school age children not stringely TST tested, and in older perss with or without stringe testing protecti was weaker (VE 41% and VE <20% respectively).ref 5 Prevei of Primary M.Tb infecti: A systematic review and metaanalysis of 14 observatial studies in which 3,855 child coacts (age <18 years) of adults with PTB underwe ierfer gamma release assay (IGRA) to determine M.Tb infecti status, and prevalence of IGRA positivi was compared amg those with and without previous BCG vaccinati. Prior BCG vaccinati was associated with 19 27% lower prevalence in TB infecti in the child coacts. In 6 of those studies with follow up for disease progressi amg those already infected (IGRA+) at studies) and n-stringe testing (2 studies), most studies of low bias. A multivariable analysis of efficacy by latitude that included age, tuberculin testing and diagnostic bias, did not show a statistically significa difference between degrees (RR 1.17; 95%CI ) or 0-20 degrees (RR 1.73; 95%CI ), compared to >40 degrees latitude. 5 3

34 Table 5 BCG efficacy and effectiveness Harms of the Are the aicipated effects small? enrolme, BCG vaccinated children had 58% (95% CI 23-77%) less progressi to any active TB compared to unvaccinated children. 6 BCG vaccinati in immunocompete infas is csidered as safe. 1 A systematic review analyzed adverse eves following BCG immunizati. There was substaial variati in the reported rate of lymphadenitis across couries and across periods, ranging from as low as 0.41 per 1,000 vaccinated children in Saudi Arabia in 2012 to as much as 308 per 1,000 in HIV positive vaccinated children in Haiti in There was substaial variati in the reported rate of disseminated BCG across couries and across periods, ranging from 1.81 per 1,000 in South Africa to 167 per 1,000 in France. 7 Balance between benefits and harms What is the overall quali of this evidence for the critical outcomes? both neither Unclear Effectiveness of the included studies Very low Low comparis Moderate High Safe of the BCG is safe and reduces various forms of TB in children and young adults. The quali of the evidence for the efficacy against TB disease was moderate. The quali evidence for the efficacy against primary TB infecti was low. There is a pauci of evidence comparing the effectiveness of differe BCG products. included studies Very Moderate Low low High The evidence was low to moderate quali due to estimates from 6 Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, et al. Effect of BCG vaccinati against Mycobacterium tuberculosis infecti in children: systematic review and meta-analysis. BMJ. 2014;349(aug04_5):g4643. Available accessed September Uthman et al. Systematic review safe of BCG vaccinati. available at accessed September